1. Field of the Invention
The present invention relates to novel 2-substituted-2-cyclopentanones. More specifically, the present invention relates to 2-substituted-2-cyclopentenones having pharmacological activities such as an excellent antitumor activity, and an excellent bone formation acceleration activity, and to an anti-tumor agent and a bone formation accelerator.
2. Description of the Related Art
Prostaglandins are compounds having specific biological activities such as platelet aggregation inhibitory activities and hypotensive activities, and are naturally occurring substances which are useful as therapeutical agents for peripheral circulatory organ system diseases in current medical treatments. Among these prostaglandins, prostaglandins A are known to have a double bond in the cyclopentane ring; for example, prostaglandin A.sub.2 is considered to be a medicament having hypotensive activities (see E. J. Corey et al, J. Amer. Chem. Soc., 95, 6831, 1973).
Also, since prostaglandins A inhibit potential DNA synthesis, the possibility of using prostaglandins A as an antitumor agent has been reported (see Biochem. Biophys. Res. Commun., 87, 795, 1979; W. A. Turner et al, Prostaglandins and Cancer: First International Conference 365-368, 1982.
European Unexamined Published Patent Publication No. 0106576 (published on Apr. 25, 1984), disclosed 4,5-substituted 2-cyclopentenones including prostaglandins A, among which are 5-alkylidene-4-substituted-2-cyclopentenones represented by the formula: ##STR3## wherein W represents a hydrocarbon group having 1 to 12 carbon atoms which also may be substituted, and Y represents a hydrocarbon group having 1 to 12 carbon atoms which also may be substituted and 5-(1-hydroxyhydrocarbon)-4-substituted-2-cyclopentenones of the formula: ##STR4## wherein W' and Y' are the same as W and Y, respectively. Further, it is disclosed that these compounds are useful for the treatment of malignant tumors.
Also, European Unexamined Published Patent Publication No. 0131441 (published on Jan. 16, 1985), disclosed 5-alkylidene-2-halo-4-substituted-2-cyclopentenones of the formula: ##STR5## wherein Ra represents a substituted or non-substituted hydrocarbon having 1 to 12 carbon atoms or a substituted or non-substituted phenyl group; Rb represents a substituted or non-substituted hydrocarbon having 1 to 12 carbon atoms; and X represents a halogen atom, and further, that these compounds are similarly effective for the treatment of malignant tumors.
Further, prostaglandins D and J different from prostaglandins A are known to be useful as antitumor agents (Japanese Unexamined Patent Publication (Kokai) 58-216155 and proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. U.S.A.), 81, 1317-1321, 1984).
Also, prostaglandin analogues represented by the formula: ##STR6## and isolated from coral produced in Okinawa [Okinawa soft coral: clavularia viridis] are known to have an antiinflammatory activity and antitumor activity as physiological activities thereof [see Kikuchi et al, Tetrahedron Lett., 23, 5171, 1982; Kobayashi et al, Tetrahedron Lett., 23, 5331, 1982; Masanori Fukushima, Cancer and Chemotherapy, 10, 1930, 1983).
Japanese Unexamined Patent Publication (Kokai) No. 59-59646 disclosed culavulon derivatives including the above natural products of the formula: ##STR7## R.sup.1 and R.sup.2 together represent a keto group, or one thereof is a hydrogen group and the other is hydroxy group, R.sup.3 is a hydrogen atom or acetoxy group, n is 0 or 1, n being 0 when there is a double bond between the positions 8 and 12, a, b, c, d, and e are each 1 or 2, and the dotted line denotes a single bond or double bond between c and d, and that these compounds are useful as antiinflammatory agents.
Japanese Unexamined Patent Publication (Kokai) No. 59-184158 disclosed, as a compound having a similar antiinflammatory activity, culavulon derivatives of the formula: ##STR8## wherein Ac denotes an acetyl group.
Japanese Unexamined Patent Publication (Kokai) No. 60-4129 disclosed that the culavalon derivatives included in the above two formulae are useful as antitumor agents.
E. J. Corey et al synthesized the culavalon derivatives represented by the following formula: ##STR9## (Journal of the American Chemical Society (J. Am. Chem. Soc.), 106, 3384, 1984).
Nagaoka et al similarly synthesized culavulon derivatives represented by the following formula: ##STR10## (Tetrahedron Letters, vol. 25, No. 33, pages 3621-3624, 1984).
Further, recently, punaglandins 1 and 2 represented by the formula: ##STR11## and the formula: ##STR12## were isolated from Telesto riisei growing on a ship's bottom at Oaf island. B. J. Baker, J. of American Chem. Soc., 107, 2976, 1985.
Also, published PCT Patent Application No. WO85-03706 (publication date: Aug. 29, 1985) disclosed punaglandins represented by the following formula: ##STR13## wherein R.sup.1 resents a hydrogen atom, C.sub.1 -C.sub.10 an alkyl group or one equivalent cation, R.sup.2, R.sup.3, R.sup.4 may be the same or different, and each represents a hydrogen atom or C.sub.2 -C.sub.10 acyl group, and the representation denotes a single bond or double bond, and that these punaglandins are useful for the therapy of malignant tumors.
Masanori Fukushima et al reported that the compounds of the following formula included in the above formula: ##STR14## have an antitumor activity (see Masanori Fukushima et al collected abstracts of the 43rd Meeting of Japanese Society of Cancer, p. 258, 1984).
Further, Japanese Unexamined Patent Publication (Kokai) No. 62-96438 disclosed 4-hydroxy-2-cyclopentenones which are culavulon analogues and punaglandin analogues of the formula: ##STR15## wherein X represents a hydrogen atom or a halogen atom; A and B represent a combination of A which is a hydrogen atom and B which is a hydroxyl group or A and B are bonded mutually to represent one bonding arm; R.sup.1 represents a substituted or non-substituted alkyl group, and an alkenyl group or alkynyl group having 1 to 10 carbon atoms; R.sup.2 represents a substituted or non-substituted alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms; and R.sup.3 represents a hydrogen atom or a protective group for a hydroxyl group; with the proviso that R.sup.2 cannot be 2-octenyl, 8-acetoxy-2-octenyl or 2,5-octadienyl and that these compounds are useful for the therapy of malignant tumors.
Furthermore, the bone metabolism of an average healthy human is considered to be valid when a good balance is maintained between repeated bone resorption with an osteoclast and bone formation with an osteoblast, and when this balance between bone resorption and bone formation is disturbed, diseases such as osteoporosis or osteomalacia may occur. As the therapeutical agents for such bone diseases, active type vitamin preparations, calcitonin preparations, diphosphonic acid preparations, estrogen preparations, and calcium preparations may be employed, but although many of these preparations have been reported to inhibit bone resorption, etc., none have clearly manifested an effect of accelerating bone formation. Further, the effects of these preparations are uncertain, and accordingly, there is a strong demand for the development of a drug which causes an acceleration of bone formation with osteoblast, without uncertainty about the effects thereof.
Koshihara et al. found that prostaglandin D.sub.2 has a calcification accelerating activity on human osteoblast, as reported in the Biochemical Society of Japan (Collected abstracts, p. 767, 1988), thought to be caused by the activity of .DELTA..sup.12 -prostaglandin J.sub.2 formed by a decomposition of prostaglandin D.sub.2. Nevertheless, a bone acceleration activity of the 2-substituted-2-cyclopentanones is not known.